BACKGROUND Activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) is established as a central intracellular trigger for various cardiac pathologies such as hypertrophy, heart failure or arrhythmias in animals and humans suggesting CaMKII as a promising target protein for future medical treatments. However, the physiological role of CaMKII is scarcely well defined. AIM & METHODS To investigate the role of CaMKII in hyperacute pressure overload, we evaluated the effects of pressure overload induced by transverse aortic constriction (TAC) on survival, cardiac function, protein expression and excitation-contraction coupling (ECC) in female WT littermate vs. AC3-I mice 2 days after TAC (2d post TAC). AC3-I mice express the CaMKII inhibitor autocamtide-3 related inhibitory peptide (AiP) under the control of the α-myosin heavy chain promotor in the heart. RESULTS CaMKII activation is significantly increased in WT TAC vs. sham mice 2d post TAC. Interestingly, survival is significantly reduced in AC3-I animals within the first five days after TAC compared to WT TAC littermates, while systolic cardiac function is markedly reduced in AC3-I TAC vs. AC3-I sham mice, but preserved in WT TAC vs. WT sham mice. Proteins regulating ECC such as ryanodine receptors (RyR2) and phospholamban (PLB) are hypophosphorylated at their CaMKII phosphorylation site in AC3-I TAC mice, but hyperphosphorylated in WT TAC mice compared to controls. In isolated cardiomyocytes fractional shortening is significantly impaired in AC3-I compared to WT mice 2d post TAC, and CaMKII incubation with AiP mimics the AC3-I phenotype in cardiomyocytes from WT TAC mice in vitro. In summary, this suggests cardiac dysfunction due to CaMKII inhibition as a potential cause of increased mortality in AC3-I TAC mice. However, proarrhythmic spontaneous Ca2+ release events (SCR) appear less frequent in cardiomyocytes from AC3-I TAC mice than in WT TAC mice. CONCLUSIONS Our data indicate that excessive CaMKII inhibition as present in AC3-I transgenic mice leads to an impaired adaptation of ECC to hyperacute pressure overload resulting in diminished cardiac contractility and increased death. Thus, our data suggest that in pressure overload the activation of CaMKII is a pivotal, but previously unknown part of hyperacute stress physiology in the heart, while CaMKII inhibition, albeit potentially antiarrhythmic, can be detrimental. This should be taken into account for future studies with CaMKII inhibitors as therapeutic agents.

中文翻译：

---

Ca2 + /钙调蛋白依赖性蛋白激酶II在超急性压力超负荷中至关重要。

背景技术Ca2 + /钙调蛋白依赖性蛋白激酶II（CaMKII）的激活被确立为动物和人类中各种心脏疾病（例如肥大，心力衰竭或心律不齐）的中心细胞内触发因素，提示CaMKII是未来治疗的有希望的靶蛋白。然而，几乎没有明确CaMKII的生理作用。目的和方法为研究CaMKII在超急性压力超负荷中的作用，我们评估了横渡主动脉缩窄（TAC）诱发的压力超负荷对女性WT同窝仔成活率，心脏功能，蛋白质表达和兴奋收缩偶联（ECC）的影响TAC后2天（TAC后2天），AC3-I小鼠。AC3-I小鼠在心脏中的α-肌球蛋白重链启动子的控制下表达CaMKII抑制剂autocamtide-3相关抑制肽（AiP）。结果与TAC后第2天的假小鼠相比，WT TAC中的CaMKII激活显着增加。有趣的是，与WT TAC同窝仔相比，AC3-I动物在TAC后头五天内的存活率显着降低，而收缩期心脏功能在AC3-I TAC和AC3-I假手术小鼠中明显降低，但在WT TAC vs WT假鼠。在AC3-I TAC小鼠中，调节ECC的蛋白（如ryanodine受体（RyR2）和phosphoramban（PLB））在其CaMKII磷酸化位点处被磷酸化，但在WT TAC小鼠中，与对照相比，它们的磷酸化水平更高。与TAC后2天的WT小鼠相比，在分离的心肌细胞中AC3-I的分数缩短明显受损，CaMKII和AiP孵育可模拟WT TAC小鼠体外心肌细胞的AC3-I表型。总之，这表明由于CaMKII抑制引起的心脏功能障碍是AC3-I TAC小鼠死亡率增加的潜在原因。但是，与WT TAC小鼠相比，AC3-I TAC小鼠的心肌细胞中心律失常自发性Ca2 +释放事件（SCR）出现的频率较低。结论我们的数据表明，如在AC3-I转基因小鼠中存在的过度的CaMKII抑制作用会导致ECC对超急性压力超负荷的适应性受损，从而导致心脏收缩力降低和死亡增加。因此，我们的数据表明，在压力超负荷情况下，CaMKII的激活是心脏中超急性应激生理的关键但先前未知的部分，而CaMKII的抑制（尽管可能具有抗心律失常作用）可能是有害的。